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Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.
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Pele , Sinucleinopatias , alfa-Sinucleína , Idoso , Feminino , Humanos , Masculino , alfa-Sinucleína/análise , Biópsia , Estudos Transversais , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/patologia , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/patologia , Sinucleinopatias/diagnóstico , Sinucleinopatias/patologia , Fosforilação , Pele/química , Pele/patologia , Insuficiência Autonômica Pura/diagnóstico , Insuficiência Autonômica Pura/patologia , Reprodutibilidade dos Testes , Adulto , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Método Simples-Cego , Estudos ProspectivosRESUMO
Dementia due to Parkinson's disease and Alzheimer's disease are associated with behavioural and psychological symptoms, including psychosis. Long-term management presents a challenge for health care providers and caregivers. Symptoms of psychosis include hallucinations and delusions; if untreated, these can lead to institutionalisation, decreased quality of life, and significant patient and caregiver distress. A critical step in the effective management of dementia-related psychosis (DRP) is the identification and diagnosis of affected patients. The lack of a standardised diagnostic approach presents a barrier to treatment and there are no consensus guidelines for DRP. Furthermore, there are no approved therapies for the treatment of DRP. Antipsychotic medications are often prescribed off-label, even though some are associated with an increased risk of adverse events or mortality. We present currently available screening tools and guidelines for the diagnosis and treatment of Parkinson's disease psychosis and DRP in the context of what is needed for effective management of psychosis.KEY POINTSWe present currently available screening tools and guidelines for Parkinson's disease psychosis and dementia-related psychosis, and discuss the unmet need for simple clinical diagnostic tools and treatment guidelines.The identification of psychosis is variable across different settings and specialties, without a unified approach to screening, definition, or diagnosis.Currently used tools for defining and assessing psychosis in a research setting are usually too cumbersome for everyday clinical practice.The development of a standardised set of diagnostic criteria would provide clinicians the opportunity to improve the detection, treatment, and quality of life of patients and their caregivers.
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Doença de Alzheimer , Antipsicóticos , Doença de Parkinson , Transtornos Psicóticos , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia , Qualidade de Vida , Piperidinas/efeitos adversos , Ureia/efeitos adversos , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/terapia , Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/efeitos adversosRESUMO
Aim: To assess the overall satisfaction level of movement disorder specialists using a virtual platform during the COVID-19 pandemic. Methods: This was a multicenter cross-sectional survey for a 6-month period during the beginning of the COVID-19 pandemic. Movement disorder specialists, who utilized telehealth visits from March 2020 to August 2020, were included. The study surveys, including provider's satisfaction with the care that they were able to provide and visit quality, were completed by the provider after each visit. Results: A total of 206 visits, provided by movement disorder specialists, were analyzed. Zoom was the most popular platform used for remote visits (70, 34%). A backup platform was not needed in the majority of movement disorder visits (171, 83%). The majority of physicians were very satisfied or satisfied with the care provided (72.9%) and visit quality (61%). Conclusions: The satisfaction level of specialists using telemedicine during COVID-19 was high despite having encounters with elderly patients with cognitive impairment or lacking advanced skills with technology.
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BACKGROUND: Continuous, subcutaneous (SC) levodopa/carbidopa infusion with ND0612 is under development as a treatment for patients with Parkinson's disease (PD) and motor fluctuations. OBJECTIVE: Evaluate 1-year safety data. METHODS: BeyoND is an open-label study evaluating the long-term safety of two ND0612 dosing regimens. RESULTS: Of the 214 enrolled patients (24-hour SC infusion: n = 90; 16-hour SC infusion: n = 124), 120 (56%) completed 12 months of treatment. Leading causes for study discontinuation were consent withdrawal (19.6%) and adverse events (17.3%). Rates of discontinuation were reduced from 49% to 29% after a protocol revision and retraining. Systemic safety was typical for PD patients treated with levodopa/carbidopa. Most patients experienced infusion site reactions, particularly nodules (30.8%) and hematoma (25.2%), which were judged mostly mild to moderate and led to discontinuation in only 10.3% of the participants. CONCLUSIONS: Subcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Levodopa , Doença de Parkinson , Antiparkinsonianos/efeitos adversos , Carbidopa/efeitos adversos , Combinação de Medicamentos , Géis , Humanos , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológicoRESUMO
PURPOSE OF REVIEW: In autonomic failure, neurogenic orthostatic hypotension (nOH) and neurogenic supine hypertension (nSH) are interrelated conditions characterized by postural blood pressure (BP) dysregulation. nOH results in a sustained BP drop upon standing, which can lead to symptoms that include lightheadedness, orthostatic dizziness, presyncope, and syncope. nSH is characterized by elevated BP when supine and, although often asymptomatic, may increase long-term cardiovascular and cerebrovascular risk. This article reviews the pathophysiology and clinical characteristics of nOH and nSH, and describes the management of patients with both nOH and nSH. RECENT FINDINGS: Pressor medications required to treat the symptoms of nOH also increase the risk of nSH. Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other. The management of patients with nOH who also have nSH can be challenging and requires an individualized approach to balance the short- and long-term risks associated with these conditions. Approaches to manage neurogenic BP dysregulation include nonpharmacologic approaches and pharmacologic treatments. A stepwise treatment approach is presented to help guide neurologists in managing patients with both nOH and nSH.
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Doenças do Sistema Nervoso Autônomo , Droxidopa , Hipertensão , Hipotensão Ortostática , Pressão Sanguínea , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipotensão Ortostática/complicações , Hipotensão Ortostática/epidemiologia , Hipotensão Ortostática/terapiaRESUMO
[This corrects the article DOI: 10.1016/j.prdoa.2023.100223.].
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Introduction: Parkinson's disease (PD) is associated with increased mortality risk (MR), reflecting progression of motor and nonmotor symptoms. PD psychosis (PDP), a common nonmotor symptom, increases with prolonged disease and elevates the MR of PD even further. Pimavanserin is the only FDA-approved treatment for PDP. This review summarizes real-world evidence around the MR of patients with PDP treated with pimavanserin versus off-label atypical antipsychotics. Methods: A PubMed search was conducted using the following search terms: pimavanserin AND antipsychotic AND mortality AND Parkinson's disease AND psychosis. Inclusion criteria specified the entry of retrospective, observational, and open-label studies comparing pimavanserin to atypical antipsychotics or untreated controls. Results: A total of 10 of the 32 articles met inclusion criteria. Among five comparisons of pimavanserin with atypical antipsychotics, two were large (n = 21,719; n = 21,975), representative, Medicare-database studies, which demonstrated comparable or lower all-cause pimavanserin MR. Among three pimavanserin versus control studies, two reported lower or comparable pimavanserin MR and one, long-term care study reported higher MR for pimavanserin versus non-pimavanserin treated patients with unknown PDP status. Two open-label extensions reported pimavanserin mortality rates of 6.45 and 18.8 deaths per 100 patient-years, which are comparable to, or lower than, mortality rates for PD, PDP, and other atypical antipsychotics. Most studies (70 %; 7 of 10) demonstrated pimavanserin's MR was lower than or similar to other atypical antipsychotics or untreated controls. Conclusions: Pimavanserin did not increase the MR in PDP. Pimavanserin's MR appears to be comparable to or lower than other atypical antipsychotics prescribed for PDP, including quetiapine.
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BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.
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Antiparkinsonianos , Apomorfina , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Apomorfina/administração & dosagem , Apomorfina/efeitos adversos , Apomorfina/farmacologia , Administração Sublingual , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Resultado do TratamentoRESUMO
Introduction: In the United States (US), prophylactic treatment with the antiemetic trimethobenzamide has been used before initiating apomorphine therapy. However, US trimethobenzamide stores have been depleted, leaving uncertainty regarding whether antiemetic pretreatment is needed. Methods: This modified Delphi panel aimed to inform circumstances when apomorphine is initiated without antiemetic pretreatment. During Round 1, a panel of 9 US movement disorder specialists rated the appropriateness of prescribing apomorphine therapy with and without antiemetic pretreatment across 192 patient scenarios and were able to review their scores in relation to other scores. During the Round 2, consensus was defined for each scenario as either strong (>75 % agreement) or moderate (66 % agreement). Results: There was strong consensus on 118 of 192 scenario's (97 as appropriate and 21 as inappropriate), moderate consensus on 29 scenarios, some agreement on 32 scenarios, and lack of agreement on 13 scenarios. In the absence of an antiemetic, there was strong consensus that titration schedules should be flexible and based on dose response. However, the group only reached moderate consensus on the speed of titration, highlighting the need for more systematic information on this area. In the presence of an antiemetic, panelists considered usual initial dosing and flexible titration to be appropriate in most scenarios except for when the patient is already experiencing dopaminergic adverse events. Conclusions: Experts generally reached consensus that apomorphine can usually be prescribed without antiemetic pretreatment. Recommendations described here reflect the areas of greatest agreement among a panel of experts based on current available evidence.
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BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.
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Discinesias , Doença de Parkinson , Masculino , Humanos , Feminino , Doença de Parkinson/tratamento farmacológico , Levodopa/uso terapêutico , Carbidopa/efeitos adversos , Antiparkinsonianos/uso terapêutico , Infusões Subcutâneas , Discinesias/tratamento farmacológico , Método Duplo-Cego , Resultado do TratamentoRESUMO
Sialorrhea, or drooling, is defined as excessive saliva accumulation and unwanted loss of saliva from the mouth or over the tongue and into the pharynx. It constitutes one of the most frequent and bothersome complaints of patients with Parkinson's disease (PD), affecting up to 84% of them. Sialorrhea is a distressing and challenging condition that may result in social isolation, embarrassment, depression, skin infections, poor oral health, and aspiration pneumonia. To better understand the burden of sialorrhea on patients with PD, Parkinson's Europe carried out a worldwide patient survey which showed that sialorrhea remains an underrecognized and undertreated issue in patients with PD. This is especially problematic because effective therapeutic options are available. This article presents the results of the Parkinson's Europe Sialorrhea Survey, which were considered by a multidisciplinary panel of experts to provide recommendations for improving the awareness, diagnosis, management, and treatment of sialorrhea in patients with PD. A shift in the treatment paradigm for sialorrhea in patients with PD is emerging. It is essential to better educate patients, family members, caregivers, and healthcare professionals about sialorrhea; to engage all those involved to actively discuss sialorrhea and measure its impact on quality of life; and to recognize the role of botulinum toxin and speech and language therapy as first-line therapies.
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Introduction: Pretreatment with the antiemetic trimethobenzamide has been recommended practice in the United States (US) to address the risk of nausea and vomiting during initiation of apomorphine treatment. However, trimethobenzamide is no longer being manufactured in the US, and despite the recent update to the US prescribing information, there may be uncertainty regarding how to initiate apomorphine. Methods: To better understand why antiemetic pretreatment was recommended and if it is necessary when initiating apomorphine therapy, we performed a literature review of subcutaneous apomorphine therapy initiation with and without antiemetic pretreatment in patients with PD. Results: Three studies were identified as providing relevant information on antiemetic prophylaxis with initiation of injectable apomorphine. The first study demonstrated that nausea was significantly more common in patients who received 3-days of trimethobenzamide pretreatment compared with those who did not, while the primary endpoint of second study found no significant effect on the binary incidence of nausea and/or vomiting on Day 1 of apomorphine treatment. In the third study, which used a slow titration scheme for apomorphine, transient nausea was reported in just 23.1% of the antiemetic nonusers. Conclusions: Based on the reviewed trials and our clinical experience, we suggest that subcutaneous apomorphine therapy can be initiated using a slow titration scheme without antiemetic pretreatment.
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Aim: Evaluate timing of motor improvement with carbidopa/levodopa (CD/LD) and apomorphine sublingual film (SL-APO) in patients with Parkinson's disease and OFF episodes. Methods: A post hoc pooled analysis from two studies assessed Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) scores and investigator-rated FULL ON. Results: At 15 and 30 min following the prescribed first daily CD/LD dose, mean improvements in MDS-UPDRS-III scores were -6.7 and -16.3, respectively, and FULL ON was achieved by 6.5 and 41.8% of patients. Following an optimized SL-APO dose, mean improvements in MDS-UPDRS-III scores were -13.9 and -22.9, and FULL ON was achieved by 34.7 and 81.0% of patients. Conclusion: Concomitant administration of SL-APO with carbidopa/levodopa may be useful for delayed ON.
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Levodopa , Doença de Parkinson , Humanos , Levodopa/uso terapêutico , Carbidopa/uso terapêutico , Apomorfina , Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Combinação de MedicamentosRESUMO
BACKGROUND: Transcutaneous afferent patterned stimulation (TAPS) is a noninvasive neuromodulation therapy that improves hand tremor in essential tremor (ET) patients. The benefits of TAPS in ET patients with high unmet need (severe tremor, non-responsive to medication, age ≥65 years) and early responders (substantial TAPS tremor improvement in the first month) remains unknown. RESEARCH DESIGN AND METHODS: Literature was surveyed for TAPS studies to assess the response in the high unmet need subgroup and early responders. Analyses were performed using previously collected Tremor Research Group Essential Tremor Rating Scale (TETRAS) scores, Bain & Findley activities of daily living (BF-ADL) scores, and tremor power. RESULTS: Significant differences in BF-ADL and TETRAS improvement were observed with TAPS over sham for the high unmet need subgroup in a randomized controlled study (P<0.03). During a 3-month open-label study, the high unmet need subgroup and early responders showed significant improvements in BF-ADL, TETRAS, and tremor power (P<0.001). Analysis of previous real-world evidence demonstrated that early responders maintained effectiveness and usage at 3 and 12 months (P<0.001). CONCLUSIONS: TAPS showed comparable improvements in ET with high unmet need as reported in the original studies, and greater efficacy in early responders. These findings inform patient selection and the trial process for identifying TAPS responders.
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Estimulação Encefálica Profunda , Tremor Essencial , Idoso , Humanos , Atividades Cotidianas , Tremor Essencial/terapia , Manejo da Dor , Resultado do Tratamento , Tremor , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Most patients with Parkinson's disease (PD) receiving levodopa (LD)/DOPA decarboxylase inhibitors develop motor fluctuations with an increasing amount of OFF time, negatively impacting patient quality of life. Herein, we review the evidence supporting the substantial, yet underappreciated contribution of delays in time to ON (including delayed ON and no ON) to total daily OFF time. Most clinical studies use patient diaries that do not capture time to ON and wearing OFF separately as related to LD dosing, and consequently, most OFF time has generally been attributed to wearing OFF. Hence, most treatment regimens focus on reducing wearing OFF by changing LD dosing/formulations and/or using "ON-extenders" (eg, catechol-o-methyltransferase inhibitors, monoamine oxidase-B inhibitors, extended-release amantadine, and adenosine A2A receptor antagonists). However, the literature describing approved treatments for PD that has focused on delays in time to ON is sparse and suggests this type of OFF may comprise more than twice the amount of total daily OFF time as wearing OFF. Here, we advocate for the importance of measuring and adequately addressing delays in time to ON and build support for the consistent inclusion of the time to ON measurement in future clinical trials.
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Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Qualidade de Vida , Catecol O-Metiltransferase , Levodopa/uso terapêuticoRESUMO
Dopamine agonists (DAs) have demonstrated efficacy for the treatment of Parkinson's disease (PD) but are limited by adverse effects (AEs). DAs can vary considerably in their receptor subtype selectivity and affinity, chemical composition, receptor occupancy, and intrinsic activity on the receptor. Most currently approved DAs for PD treatment primarily target D2/D3 (D2-like) dopamine receptors. However, selective activation of D1/D5 (D1-like) dopamine receptors may enable robust activation of motor function while avoiding AEs related to D2/D3 receptor agonism. Full D1/D5 receptor-selective agonists have been explored in small, early-phase clinical studies, and although their efficacy for motor symptoms was robust, challenges with pharmacokinetics, bioavailability, cardiovascular AEs, and dyskinesia rates similar to levodopa prevented clinical advancement. Generally, repeated dopaminergic stimulation with full DAs is associated with frontostriatal dysfunction and sensitization that may induce plastic changes in the motor system, and neuroadaptations that produce long-term motor and nonmotor complications, respectively. Recent preclinical and clinical studies suggest that a D1/D5 receptor-selective partial agonist may hold promise for providing sustained, predictable, and robust motor control, while reducing risk for motor complications (e.g., levodopa-induced dyskinesia) and nonmotor AEs (e.g., impulse control disorders and excessive daytime sleepiness). Clinical trials are ongoing to evaluate this hypothesis. The potential emerging availability of novel dopamine receptor agonists with selective dopamine receptor pharmacology suggests that the older terminology "dopamine agonist" may need revision to distinguish older-generation D2/D3-selective agonists from D1/D5-selective agonists with distinct efficacy and tolerability characteristics.
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BACKGROUND: Nausea is common upon initiating dopamine agonists in patients with Parkinson's disease (PD); however, pretreatment with an antiemetic is recommended only when initiating apomorphine formulations. OBJECTIVE: Evaluate the need for prophylactic antiemetic use during dose optimization of apomorphine sublingual film (SL-APO). METHODS: A post hoc analysis of a Phase III study evaluated nausea and vomiting treatment-emergent adverse events in patients with PD who underwent SL-APO dose optimization (10-35âmg; 5-mg increments) to achieve a tolerable FULL ON. Frequencies of nausea and vomiting were described for patients who did versus did not use an antiemetic during dose optimization and by patient subgroups based on extrinsic and intrinsic factors. RESULTS: Overall, 43.7% (196/449) of patients did not use an antiemetic during dose optimization; most of these patients (86.2% [169/196]) achieved an effective and tolerable SL-APO dose. In patients who did not use an antiemetic, nausea (12.2% [24/196]) and vomiting (0.5% [1/196]) were uncommon. An antiemetic was used in 56.3% (253/449) of patients, with 17.0% (43/253) and 2.4% (6/253) experiencing nausea and vomiting, respectively. All events of nausea (14.9% [67/449]) and vomiting (1.6% [7/449]) were of mild-to-moderate severity except for 1 event each. Irrespective of antiemetic use, among patients without baseline dopamine agonist use, nausea and vomiting rates were 25.2% (40/159) and 3.8% (6/159); in those already using dopamine agonists, rates were 9.3% (27/290) and 0.3% (1/290). CONCLUSION: Prophylactic treatment with an antiemetic is not necessary for most patients who initiate SL-APO for the treatment of OFF episodes in PD.
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Antieméticos , Doença de Parkinson , Humanos , Antieméticos/uso terapêutico , Apomorfina/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Náusea/prevenção & controle , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Vômito/prevenção & controle , Vômito/induzido quimicamente , Vômito/tratamento farmacológicoRESUMO
Background: Many patients with Parkinson's disease (PD) experience action tremor (including postural and kinetic tremors) that impair activities of daily living. Transcutaneous afferent patterned stimulation (TAPS) is a non-invasive neuromodulation therapy that modulates tremorgenic activity at the ventral intermediate nucleus (VIM). Most TAPS evidence evaluated relief of action tremor associated with essential tremor (ET). This study evaluated whether TAPS results in similar relief of action tremor associated with PD. Methods: Forty PD patients with action tremors were enrolled in a prospective, single-arm, open-label study with four weeks of unsupervised at-home TAPS sessions in the dominant hand twice daily in between supervised TAPS sessions at two telemedicine appointments. The primary endpoint was change in tremor power as measured by the on-board accelerometer before and immediately after a stimulation session. Additional study endpoints included change in Movement Disorder Society-Sponsored Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS), change in Bain and Findley Activities of Daily Living (BF-ADL) scale, and clinician and patient global impressions of improvement (CGI-I and PGI-I). Results: TAPS reduced tremor power by 64% (54%-79%) (median (interquartile range), p < 0.001), with 79% of patients experiencing at least 50% reduction. When comparing pre-stimulation scores at visit 1 to post-stimulation scores at visit 2, TAPS improved per-task MDS-UPDRS III ratings of postural and kinetic tremors (0.6 ± 0.5, t(34) = 7.05, p < 0.001) and per-task patient-ratings of BF-ADL ADL upper limb motion ratings (0.5 ± 0.5, t(34) = 5.69, p < 0.001). Clinicians reported improvement in 78-83% of patients and 75-80% of patients reported improvement. Adverse events, most commonly skin reaction at the stimulation site, occurred in 18% of patients. Conclusion: Objective, clinician-rated, and patient-rated assessments demonstrated that TAPS provided clinically meaningful relief of action tremor in patients with PD.
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Tremor Essencial , Doença de Parkinson , Humanos , Atividades Cotidianas , Tremor Essencial/terapia , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Estudos Prospectivos , TremorRESUMO
Background and Objectives: Ulotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT1A receptor agonist activity currently in phase 3 clinical development for the treatment of schizophrenia. In this exploratory, flexibly dosed study, ulotaront was evaluated for the treatment of Parkinson disease psychosis (PDP). Methods: Patients with PDP requiring antipsychotic therapy were randomized, double-blind to ulotaront (25, 50, or 75 mg/d) or placebo. Mixed Model for Repeated Measures was used to assess change from baseline in the Scale for the Assessment of Positive Symptoms for Parkinson Disease (SAPS-PD) at 6 weeks (primary end point). Results: The efficacy analysis sample comprised 38 patients (ulotaront, n = 24; placebo, n = 14). SAPS-PD total scores were numerically reduced in ulotaront-treated vs placebo-treated patients from week 1 to week 6: Least squares mean (95% confidence interval) difference in change from baseline at week 6 was -1.1 (-6.5, 4.3, p = 0.681). PDP symptom complete remission (≥100% improvement [reduction] from baseline in SAPS-PD total score) was observed in 25% of ulotaront-treated vs 0% of placebo-treated patients. SAPS-PD and Neuropsychiatric Inventory hallucinations subscales were numerically reduced vs placebo, and SAPS-PD total scores were reduced in patients with greater cognitive impairment (baseline Mini-Mental State Examination [MMSE] scores ≤24). Ulotaront improved Scales for Outcomes in Parkinson Disease Sleep Scale - Daytime Sleepiness scores (p = 0.022). There was no worsening of Unified Parkinson Disease Rating Scale Part III motor score, MMSE, or vital signs. Adverse events (≥10%) with ulotaront vs placebo included hallucinations (24% vs 14%), confusional state (20% vs 14%), dizziness (16% vs 7%), nausea (12% vs 7%), and falls (12% vs 21%). Discussion: In this exploratory pilot study, ulotaront may decrease PDP symptoms without worsening motor function, particularly in patients with cognitive impairment. Trial Registration Information: ClinicalTrials.gov identifier: NCT02969369; submitted: November 17, 2016; study start date: December 31, 2016. Classification of Evidence: This Class II study was an exploratory pilot study that was underpowered to detect a statistically significant difference between ulotaront and placebo in the treatment of patients with Parkinson disease psychosis without worsening motor function.
RESUMO
Introduction: Carbidopa/levodopa enteral suspension (CLES) previously demonstrated reduction in total daily OFF from baseline by over 4 hours in advanced Parkinson's disease patients across 54 weeks. Evidence on CLES's long-term effectiveness on patterns of motor-symptom control throughout the day remains limited. Methods: We present post-hoc analyses of a large, open-label study of CLES monotherapy (N = 289). Diary data recorded patients' motor states at 30-minute intervals over 3 days at baseline and weeks 4, 12, 24, 36, and 54. Adjusted generalized linear mixed models assessed changes from baseline at each timepoint for four outcome measures: time to ON without troublesome dyskinesia (ON-woTD) after waking, motor-symptom control as measured by motor states' durations throughout the day, number of motor-state transitions, and presence of extreme fluctuations (OFF to ON with TD). Results: Patients demonstrated short-term (wk4) and sustained (wk54) improvement in all outcomes compared to baseline. At weeks 4 and 54, patients were more likely to reach ON-woTD over the course of their day (HR: 1.86 and 2.51, both P < 0.0001). Across 4-hour intervals throughout the day, patients also experienced increases in ON-woTD (wk4: 58-65 min; wk54: 60-78 min; all P < 0.0001) and reductions in OFF (wk4: 50-61 min; wk54: 56-68 min; all P < 0.0001). At weeks 4 and 54, patients' motor-state transitions were reduced by about half (IRR: 0.53 and 0.49, both P < 0.0001), and fewer patients experienced extreme fluctuations (OR: 0.22 and 0.15, both P < 0.0001). Conclusion: CLES monotherapy was associated with significant long-term reductions in motor-state fluctuations, faster time to ON-woTD upon awakening, and increased symptom control throughout the day.